The intermediate processes which couple or transduce the interaction of an effector molecule (e.g., ADP, epinephrine, 5-hydroxytryptamine, etc.) with the platelet membrane into the platelet are unknown. While each of the effector molecules mentioned may have a unique interaction with the platelet membrane they can be generalized as interacting with platelet receptors to induce an increase in intraplatelet calcium ion levels. The increase in platelet Ca2+ ion induces interaction of platelet actin and myosin and the onset of functional change. As in most cells exhibiting excitation-contraction coupling, the intermediate processes are likely to consist of inward ion movements; e.g., influx of external Ca2+, influx of Na ion. We were the first to demonstrate that ADP addition to human platelets in plasma induces an inward movement of Na ion but not Ca2 ion. On the other hand, epinephrine addition induces inward movement of Ca2 ion but not Na ion. Furthermore, addition of amiloride will inhibit the inward movement of Na ion and aggregation induced by ADP but does not affect the epinephrine response. La3 ion added to resuspended platelets inhibits the epinephrine response and Ca2 ion influx but not the o ADP response. Thus, the effector response is ion-specific. Our findings have led us to postulate that the ADP excitation-coupling mechanism consists of an increase in Na+ permeability, an dissipation of the Na ion electrochemical transmembrane gradient, associated with the inward movement of Na ion and a rise in intraplatelet o Na ion. The rise in intraplatelet Na ion acts to induce intraplatelet calcium redistribution in a manner analogous to muscle. If this view is held it follows that platelet sensitivity to ADP will be a function of the Na+ transmembrane gradient and the rate of Na ion efflux (thus, we found that ouabain, which blocks Na ion efflux induces hypersensitivity to ADP). We propose to further delineate the characteristics of ADP (and other agonists, e.g., 5-HT) induced inward movement of Na ion and to relate these characteristics to the induction of functional change.